[6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride polymorph

Abstract

The invention is concerned with a novel polymorph of [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride. This polymorph exhibits superior properties compared to the previously known forms of [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride. The [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride is an inhibitor of tyrosine kinase enzymes, and are useful in the treatment of cancer. Also disclosed are methods of making and using the novel polymorph, as well as pharmaceutical compositions containing the novel polymorph.

1. A crystalline polymorph of [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride which has a melting point onset temperature of 211° C. to 214° C. and which has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 
       
         
           
                 
               
                     
                 
                   degree 2-theta 
                 
                     
                 
                    5.7 
                 
                    9.7 
                 
                   10.1 
                 
                   11.3 
                 
                   17.0 
                 
                   17.4 
                 
                   18.9 
                 
                   19.6 
                 
                   21.3 
                 
                   22.8 
                 
                   23.6 
                 
                   24.2 
                 
                   24.7 
                 
                   25.4 
                 
                   26.2 
                 
                   26.7 
                 
                    29.3. 
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       2. The crystalline polymorph of  claim 1 , which has the x-ray powder diffraction pattern shown in  FIG. 1 . 
     
     
       3. The crystalline polymorph of  claim 1  which has an IR absorption spectrum having characteristic peaks expressed in cm −1  approximately 3277 cm −1 , 3057 cm −1 , 1627 cm −1 , 1070 cm −1 , 892 cm −1 , 873 cm −1 , 850 cm −1 , 780 cm −1 , 745 cm −1 , 725 cm −1 , and 652 cm −1 . 
     
     
       4. The compound [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride, at least 70% of which is present as the crystalline polymorph of  claim 1 . 
     
     
       5. A process for the manufacture of the crystalline polymorph as defined in  claim 1 , which process comprises reacting a compound of formula (II) 
       
         
           
           
               
               
           
         
       
       with a compound of formula (III) 
       
         
           
           
               
               
           
         
       
       in (α,α,α)-trifluorotoluene. 
     
     
       6. A pharmaceutical composition comprising the crystalline polymorph according to  claim 1  and a pharmaceutically acceptable excipient. 
     
     
       7. A method of treating non small cell lung cancer, colorectal cancer, refractory small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, head cancer or neck cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of the crystalline polymorph of  claim 1 .